Friday, August 15, 2014

SAE Reconciliation and Determining/recording the SAE Onset Date

Traditionally clinical operations and drug
safety / pharmacovigilence departments have elected to independently collect
somewhat different sets of safety data from clinical trials. For serious
adverse events (SAE), drug safety / pharmacovigilence department will collect
the information through the SAE form and the information will be maintainted in
a safety database. In clinical operation or data management departments, the
adverse events (AE) including SAEs will be collected on case report form (CRFs)
or eCRFs if it is an EDC study. For SAEs, the information from safety database
and clinical database come from the same source (the investigational
sites). During the study or at the end
of the study, the key fields regarding the SAEs from two independently
maintained databases will need to be reconciled and the key data fields must match
in both databases.

A poster by Chamberlain et al “Safety
Data Reconciliation for Serious Adverse Events (SAE)” has nicely described
the SAE reconciliation process. They stated that for these fields to be
reconciled, “some will require a one to one match with no exception, while some
may be deemed as acceptable discrepancies based on logical match. “

They also gave examples for fields which require an exact
match or logical determination are in the following Table 1

Among these fields, the onset date is the one
usually causing problems. It is due to the different interpretation of the
regulatory guidelines by the clinical operations and the drug
safety/pharmacovigilence departments. The onset date of SAE could be reported
as the first date when signs and symptoms appears or as the date when the event
meets one of the following SAE criteria (as defined in ICH
E2A).

However,
many companies and organizations (such as NIH and NCI) indicated in their SAE
completion guidelines that event start date should be the date when the
event satisfied one of the serious event criteria (for example, if criteria
“required hospitalization” was met, the date of admission to the hospital would
be the Event Start Date). If the event
started prior to becoming serious (was less severe), it should be recorded on
the AE page as non-serious AE with a different severity.

“If an AE increases in severity or frequency (worsens) after
it has been reported on an Adverse Experience Log case report form, it must be
reported as a new AE, at the increased severity or frequency, on a new AE Log. In
this case, the status outcome of the first AE will be documented as
“severity/frequency increased.” The status of the second AE will be documented as
“continuing”. The outcome date of the first AE and the onset date of the new
(worsened) AE should be the date upon which the severity or frequency increased.”

“What would an SAE’s onset date be if a patient on study
develops symptoms of congestive heart failure (CHF) on Monday and is admitted to
the hospital the following Friday?

If known, the complete onset date (month-day-year) of the
first signs and/or symptoms of
the most recent CHF episode should be recorded. In this
case, it would be Monday. If the
onset date of the first signs and/or symptoms is unknown,
the date of hospitalization or
diagnosis should be recorded.”

If the SAE onset date is recorded as the date when one of
the SAE criteria is met (this seems to be more popular in practice), it may essentially
require the splitting of the event. If an event start as non-serious and later
on meet one of the serious criteria, the same event will be recorded as two
events: one as non-serious event with onset date being the first sign and symptom date
and one as serious adverse event with the onset date being the date when one of
the SAE criteria is met. Therefore this approach results in a late onset date
and a short SAE duration; but double counting perhaps the same event.

If the SAE onset date is recorded as the date when the first
sign or symptom appears, it will result in an early onset date and a longer SAE
duration. Since SAE reporting to the regulatory authorities / IRBs is based on the
SAE onset date, this may be more stringent in meeting the SAE reporting
requirement.